Human Papilloma Virus – Common but with dire potential consequences

Human Papilloma Virus (HPV) is a virus that infects the skin surface of oral, anal and genital cavities. Manifestation of infection is usually transient with patients not expressing symptoms. However, prolonged infection periods and/or persistent infection with certain strains of HPV can lead to more visual and serious manifestations such as genital warts, squamous intraepithelial lesions (SIL), and Carcinomas (Cervical Cancer).

HPV is the most Common Sexually Transmitted Infection (STI)
 The American Centre for Public Health Research and Evaluation (CPHRE) in 2005 estimated a prevalence rate of 20 million people and incidence of 6.5 million annually for HPV in the United States, making HPV the most common sexually transmitted infection. Worldwide, the conservatively estimated prevalence of genital HPV infection is 326 million among adult women. The organisation further estimates 80% of sexually active women and men will acquire HPV infection at some point of their life. The majority of HPV infection cases do not require medical intervention as the patient overcomes the infection himself or herself. However infection with high risk certain strains of the virus and or persistence infection may result in pre-invasive changes and development of anogenital cancer, the most common form being cervical cancer in women.

HPV Becomes Cervical Cancer – with alarming mortality rates
The CPHRE report estimates from 14,000 annual cases of cervical cancer in the U.S., 5,000 will die from the disease and worldwide from an estimated 450,000 annual (reported) cases, 200,000 will die as a direct result. In Australia, cervical cancer is the eleventh most common cancer in women, the improvement mostly due to highly developed disease screening and monitoring programs. To date there are no curative treatments for cervical cancer and HPV infection. Instead research efforts are directed towards alleviating symptoms, vaccination development and early stage detection.

High-Risk HPV the culprit, but not a direct predictor of cancer
Based on evidence presented by the Centre of Disease Control and Prevention (United States), it was concluded all cervical cancer tumour masses contain ‘high-risk type’ HPV DNA, but detection of HPV DNA alone is not a definitive diagnosis method for cervical cancer. As a result a combination of HPV DNA testing and physical cytological, colposcopy and histology diagnosis techniques must be employed.

HPV testing now becoming standardised

• In 2003 amendments were made to the Pap testing protocol to include HPV test as an adjunct with Pap testing for women aged 30 and over. This amendment was based on studies that showed 20% of women aged 30 and older that tested positive for HR-HPV were suffering from high-grade cervical disease. HPV testing is not recommended for women under the aged of 30 by clinical bodies as stated by the CPHRE 2005 report, although there remains a compelling case for those younger women who return abnormal cytology to be tested for persistent HR-HPV strains.

Pap Testing and cytology alone can be improved upon with HR-HPV Molecular Dx.
Cytology reporting following Pap smear procedures has been a reliable mainstay for the detection and treatment of cervical cell abnormalities. But recent studies have indicated that significant improvements in early HR-HPV detection and subsequent viral persistence can greatly assist medical practitioners in earlier intervention and cancer prevention. Also, HR-HPV testing has revealed false negatives from cytology testing alone.

An important Paper* published in The International Academy of Cytology journal, ACTA CYTOLOGICA by Dr. Gary Yeoh et. al. examined the value of HR-HPV DNA testing vs. cytological testing alone and revealed several key benefits inherent in the use of Molecular testing for HR-HPV DNA:

• “HPV HR DNA was positive in 25-33% of cases with normal cervical cytology…”

Due to the high prevalence of HPV infection in women, this observation does not necessarily indicate a problem with cytology, nor does it indicate an urgent call for HR-HPV testing. But it is demonstrative of the capability for Molecular testing to be significantly more sensitive in the earlier detection of infection than cytology alone. This is pertinent for those Medical practitioners who may wish to screen for persistent HR-HPV subtypes in patients who are at higher risk of infection (<30 years of age). This is not a point without cause, as postulated in the extract below:

• The prevalence of HR-HPV DNA was higher in the group 26 years or younger as compared with those >26 years for the screening population...The prevalence…was also higher in those 34 years or younger in the follow-up group…These figures suggest persistence of HR-HPV DNA in the follow-up group as compared with the screening group.

Thereby suggesting that a population currently not recommended for HR-HPV testing may well become candidates for the detection of persistent infection in the future.

• Co testing of HPV DNA and cervical cytology increases the sensitivity and decreases the false negative fraction, suggesting that co testing could be used to increase the interval of screening

A fundamental benefit for Doctors and their patients in minimising the regularity with which they have to endure the uncomfortable and invasive nature of regular PAP testing. The evidence for this claim is seen below:

• …all 334 cytology negative/HR HPV DNA positive cases were retrieved and rescreened (by cytology). This yielded 44 (revised) cases of ASCUS or more severe changes…; the (resultant) false neg. fraction in this group was 13%. For comparison, all cyto neg. /DNA neg. cases…for the year 2000 were also screened. Only 2 ASCUS cases were found in 357 cases…a false neg. fraction of 0.5%.

A profound statement of the benefit of HR-HPV screening, detailing how previously negative cytology results were retested after being found positive by a molecular test, with a subsequently revised (now positive) cytological assessment in 13% of the cases. If accompanied by persistent HR-HPV infection, these false negatives could have delivered dangerous consequences for the patients involved.

Since the advent of early HPV DNA tests, several other Papers have emerged detailing similar observations on the potential benefits of HR-HPV DNA testing either alone or in combinations with cytology.
* Yeoh, G.P.S. et al; Human Papillomavirus DNA and Liquid-Based Cervical Cytology Cotesting in Screening and Follow-up Patient Groups; (ACTA Cytologica 2006; 50:627–631); http://www.acta-cytol.com/toc/auto_abstract.php?id=22660